Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[CH2:8][C:7]2[CH:11]=[C:12]([CH3:14])[S:13][C:6]=2[S:5]1(=[O:16])=[O:15].[H][H].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH3:3][N:4]1[C:9](=[O:10])[CH:8]([C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[C:7]2[CH:11]=[C:12]([CH3:14])[S:13][C:6]=2[S:5]1(=[O:16])=[O:15]
Reactant: Cc1cc2c(s1)S(=O)(=O)N(C)C(=O)C2
Reactant: O=C=Nc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(s1)S(=O)(=O)N(C)C(=O)C2C(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a suspension of 0.82 g (34 mmol) sodium hydride in 50 mL tetrahydrofurane was added at −5° C. under N2 a solution of 5.3 g (23 mmol) 3,4-dihydro-2,6-dimethyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide in 50 mL tetrahydrofurane. After termination of the hydrogen formation 6.5 g (55 mmol) phenylisocyanate dissolved in 50 mL tetrahydrofurane were added at −5° C. After stirring at room temperature the resulting mixture was quenched with ice/water and by addition of dilute HCl and then extracted with CH2Cl2 (2 times). The combined CH2Cl2 extracts were washed, dried and concentrated to give 6 g crude product. This material was recrystallized from ethanol to give 4.8 g 3,4-dihydro-2,6-dimethyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine-4-carboxanilide 1,1-dioxide.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].C(Cl)Cl>[Cu]=O.CN(C)C=O>[CH2:11]1[O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(O)c1O
Agent: O=[Cu]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1OCO2
Yield: 79.9 %

Procedure:
138.0 g (1.0 mol) of 2,3-dihydroxybenzaldehyde, 415.0 g (3.0 mol) of potassium carbonate, 4.7 g of copper oxide, 255.0 g (3.0 mol) of methylene chloride and 1500 ml of distilled dimethylformamide are boiled for 7 hours, while stirring intensively. The reaction mixture is evaporated to dryness-in vacuo and, after addition of 1000 ml of ice-water to the residue, the mixture is extracted four times by shaking with 300 ml of methyl tert-butyl ether each time. The combined ether extracts are washed with 5% strength sodium hydroxide solution and water and dried over sodium sulphate. The methyl tert-butyl ether is then stripped off (and can be reused) and the residue is distilled in vacuo at 92°-93° C./1 mbar. 120 g (80% of theory) of 2,3-methylenedioxybenzaldehyde having a melting point of 32°-33° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1nc2ncccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cnc4ncccc4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 24 h
Yield: 22.8 %

Procedure:
3-Hydroxy-[1,8]naphthyridine-2-carboxylic acid (15 mg), 4-chloro-6,7-dimethoxyquinoline (47 mg), and 4-dimethylaminopyridine (26 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (6 mg, yield 26%).
Reaction SMILES: C(OC([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([CH:38]=[CH:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[N:27]=1)=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:47]>CO.C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:46].[ClH:47].[C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([CH:38]=[CH:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[N:27]=1)(=[NH:8])[NH2:10]
Reactant: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=N)N)c2c1

Procedure:
A solution of 570 mg of cis-N-[N,N′-bis(tert-butoxycarbonyl)]amidino-2-[2-(4-chlorostyryl)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 8 mL of methanol and 8 mL of chloroform was combined with 5 mL of a 4N solution of hydrogen chloride in ethyl acetate, and reacted at 50° C. for 48 hours. After concentrating, crystallization are performed with ethyl acetate to obtain 310 mg of the desirable compound as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[C:9]1[C:15](OC)=O.C(O)(=O)C.Cl.Cl.[CH3:29][C:30]([CH3:42])([CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:31]([O:33][CH3:34])=[O:32]>O.[Fe]>[CH3:29][C:30]([CH3:42])([CH2:35][N:36]1[CH2:41][CH2:40][N:39]([C:15]2[C:9]3=[CH:10][C:11]([S:13][CH3:14])=[CH:12][N:8]3[CH2:7][C:6]3[CH:19]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[N:20]=2)[CH2:38][CH2:37]1)[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1cc(SC)cn1Cc1cc(C)ccc1[N+](=O)[O-]
Reactant: COC(=O)C(C)(C)CN1CCNCC1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(C)cc3Cn3cc(SC)cc32)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
Treat methyl 1-(5-methyl-2-nitrobenzyl)-4-(methylsulfanyl)-1H-pyrrole-2-carboxylate (3.49 mmoles; 1.12 g) with acetic acid (15 mL) then treat with iron, powder (10.5 mmoles; 585 mg) then slowly heat in an oil bath at 80° C. After a few hours increase the oil bath temperature to 90° C. Then leave the reaction at 60° C. for 2 days. Then concentrate to dryness to remove acetic acid then treat with EtOAc and wash through a pad of silica with more EtOAc until the orange colour stops coming off. Concentrate the red eluant to dryness then treat with methanol then re-concentrate and dissolve in DCM (20 mL) and treat with phosphoryl chloride (1.0 mL). Heat the reaction in an oil bath at 50° C. overnight. Then cool the reaction to RT and treat with ice then wash with water twice and then NaHCO3 (aq). Dry the organic layer over MgSO4, filter and concentrate to a tar. Meanwhile dissolve methyl 2,2-dimethyl-3-(piperazin-1-yl)-propanoate dihydrochloride (1.60 g, 5.86 mmoles) in water then load on to a SCX-2 cartridge (2×10 g) and wash with methanol and then elute with ammonia in methanol. Concentrate the basic solution to dryness to an oil. Then dissolve this oil in acetonitrile (50 mL) and add to a mixture of the tar and potassium carbonate (1.0 g) then heat to reflux. After 2 hours, microwave the reaction to 140° C. for 2 hours. Then filter the reaction and extract with acetonitrile and acetone. Combine and concentrate the mother liquors to dryness onto silica then purify by flash chromatography silica (40 g) (10-50% EtOAc in hexane). Take the fractions which contain clean product, combine and concentrate to yield methyl 2,2-dimethyl-3-[4-(7-methyl-2-(methylsulfanyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-propanoate (418 mg; 27% yield). MS (m/z): 441.18 (M+1).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:20][C:21](=[O:31])[CH:22]([CH2:26][S:27](Cl)(=[O:29])=[O:28])[CH:23]([CH3:25])[CH3:24])(C)(C)C.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][CH:23]([CH3:25])[CH:22]([CH2:26][S:27]([N:11]1[CH2:12][CH2:13][C:14]2[N:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8][C:9]=2[CH2:10]1)(=[O:29])=[O:28])[C:21]([OH:31])=[O:20]
Reactant: c1ccc(-c2nc3c(s2)CNCC3)cc1
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)C(CS(=O)(=O)N1CCc2nc(-c3ccccc3)sc2C1)C(=O)O
Reaction time: 2 h
Yield: 74.8 %

Procedure:
2-Phenyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (0.11 g) was added to a solution of 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester (0.14 g) and triethylamine (0.3 ml) in DCM (20 ml) at room temperature. The solution was stirred for 2 h, then TFA (5 ml) was added and the mixture stirred for 1 h. The mixture was evaporated in vacuo and the residue partitioned between diethyl ether (10 ml) and saturated sodium bicarbonate (30 ml). The aqueous layer was acidified with citric acid to pH 5 and extracted with ethyl acetate (3×20 ml). The solvent was dried (MgSO4) and evaporated to give the title compound as pale yellow solid (0.15 g).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][CH2:15][C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:35][O:36][C:37]([CH2:39][CH2:40][CH2:41][CH:42]=O)=[O:38].C(O)(=O)C>C(OCC)C.O>[Si:1]([O:8][CH:9]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:42]\[CH2:41][CH2:40][CH2:39][C:37]([O:36][CH3:35])=[O:38])/[C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)C1CCCCC1
Reactant: COC(=O)CCCC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C1\CC2C(/C=C/C(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CCC2C1=O
Temperature: -70 °C
Yield: 16.2 %

Procedure:
(E)-2-(3-tert-Butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one (57 mg), prepared as described in Reference Example 14 and in the form of (±)-(E)-2β-(3α-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one, was dissolved in dry diethyl ether (0.6 ml). The solution was cooled to -70° C. under an atmosphere of argon and treated with a solution of lithium diisopropylamide in diethyl ether (0.132 ml; 1.3M) with stirring, and the mixture was stirred at -70° C. for 10 minutes. 4-Methoxycarbonylbutanal (29.6 mg) was then added to the mixture, which was stirred for a further period of 10 minutes at -70° C. The mixture was then treated with a solution of glacial acetic acid (0.05 ml) in diethyl ether (1 ml) and the mixture was allowed to warm to ambient temperature. Water and diethyl ether were added and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined diethyl ether and ethyl acetate solutions were washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The resulting residue was dissolved in dry benzene (0.6 ml). The solution was treated with methanesulphonyl chloride (0.015 ml) with stirring at the ambient temperature, and then with triethylamine (0.0255 ml), and was stirred for a further period of 2 hours. The mixture was then treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (137 mg) and stirred for 16 hours at ambient temperature. The crude mixture was then subjected to medium pressure, short column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (1:9 by volume), to give (E)-6-(3-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (12 mg), in the form of (±)-6β-[(E)-3α-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoate.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:40])[C@@H:37]([CH3:39])[NH2:38])=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:40])[C@@H:37]([CH3:39])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1Oc1ccc(N2C(=O)N[C@H](C)C2=O)cn1
Temperature: 0 °C
Yield: 174.6 %

Procedure:
In a 50 mL round-bottomed flask N1-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 44, 173.8 mg) was dissolved in dichloromethane (5 mL) to give a yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (36.5 mg, 0.298 mmol), triethylamine (0.208 mL, 1.492 mmol) and triphosgene (89 mg, 0.298 mmol) were added. The reaction mixture was stirred at 0° C. After 20 min the solvent was evaporated under vacuum to afford a yellow solid. This residue was purified by silica gel chromatography (Biotage instrument, 10 g SNAP Silica column) eluting with Cyclohexane/EtOAc from 2:1 Cyclohexane/EtOAc to 1:3 Cyclohexane/EtOAc in 20 CV; then 1:3 Cyclohexane/EtOAc for 5 CV. The collected fractions afforded the title compound as a colourless oil (162 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.[OH-].[Na+]>O.C1COCC1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc2ncccc2c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
13.0 ml (76.28 mmol) of benzyl chloroformate are added dropwise to a stirred solution, cooled to 0° C. of 10.0 g (69.36 mmol) of 6-aminoquinoline in 160 ml of water and 80 ml of THF in the course of 30 minutes, the pH being kept at 10 by simultaneous addition of a 4N NaOH solution. The mixture is subsequently stirred at 0° C. for a further 2 hours, the THF is evaporated off in vacuo and the residue is extracted with 3×50 ml of ethyl acetate. The combined organic extracts are dried over MgSO4, the solvent is evaporated off in vacuo and the residue is purified by chromatography over 450 g of silica gel (toluene:ethyl acetate 1:4). 11.60 g (60%) of the title compound are obtained as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2C=C3C=CC=C3O[C:18]=2CC(O)=O)[CH:13]=[CH:14][C:15]=1[Cl:16]>>[Br:1][C:2]1[C:3]2[O:8][CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccccc1Br
Product: Clc1ccc(-c2coc3c(Br)cccc23)cc1Cl

Procedure:
Starting with 2-bromophenol and alpha-bromo-3,4-dichloroacetophenone and using Process A as described in Examples 1 and 2, the compound 7-bromo-3-(3,4-dichlorophenyl)benzofuran is prepared. Using Process F as described in Examples 6 to 9, this compound is converted to 3-(3,4-dichlorophenyl)-7-benzofuranacetic acid, m.p. 158.5°-160° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:15][N:14]([C:16]2[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH2:13]1.C(N(CC)CC)C>>[CH:23]([NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N:14]2[CH2:13][C:12](=[O:11])[CH2:15]2)=[CH:27][CH:26]=1)([CH3:25])[CH3:24]
Reactant: CC(C)NC(=O)c1ccc(N2CC(O)C2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)NC(=O)c1ccc(N2CC(=O)C2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (1.05 mL, 12.4 mmol) in dichloromethylene (20 mL) was added dropwise dimethyl sulfoxide (1.71 mL, 24.1 mmol). The mixture was stirred at −78° C. for 10 minutes. Then a suspension of 4-(3-hydroxyazetidin-1-yl)-N-isopropylbenzamide (1.72 g, 7.34 mmol) in dichloromethylene (20 mL) was added. The mixture was stirred at −78° C. for 1 hour, and then triethylamine (7.04 mL, 50.5 mmol) was added. The mixture was stirred at −78° C. for an additional 1.5 hour. The mixture was washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The precipitates were washed with ether and collected by filtration to afford the desired product (1.32 g, 77%) which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=233.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O-:12])=[O:11])=[C:8]([CH3:13])[S:7][C:6]=2[CH:14]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([N:27]3[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]3)=[O:26])[S:24][C:17]=12.C([O-])([O-])=O.[Cs+].[Cs+].O[Li].O>>[OH:32][C@@H:29]1[CH2:30][CH2:31][N:27]([C:25]([C:23]2[S:24][C:17]3[C:18](=[N:19][CH:20]=[CH:21][C:16]=3[O:1][C:2]3[CH:3]=[CH:4][C:5]4[C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:13])[S:7][C:6]=4[CH:14]=3)[CH:22]=2)=[O:26])[CH2:28]1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)[O-]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li]O
Solvent: O
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)O
Yield: 45 %

Procedure:
This material was prepared from the reaction of methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (283 mg, 1.00 mmole) with 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4a and Cs2CO3 (977 mg, 3.00 mmole) in a manner as previously described for example 1. The crude product was then reacted with LiOH.H2O (227 mg, 5.4 mmole) in a manner similar to that described for example 11c to give a yellow solid (202 mg, 45%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.31 Hz), 8.44 (1H, d, J=8.84 Hz), 8.14, 8.07 (1H, s), 8.00 (1H, s), 7.39 (1H, dd, J=2.40, 8.97 Hz), 6.78 (1H, d, J=5.56 Hz), 4.38, 4.33 (1H, br s), 4.01-3.91 (1H, m), 3.68-3.56 (2H, m), 3.49-3.22 (2H, m), 2.81 (3H, s), 2.07-1.79 (2H, m).
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:53]2[N:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[C:30]([CH:52]=1)[C:31]([N:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([CH3:39])[C@H:34]1[CH2:40][N:41]1C(=O)C2C(=CC=CC=2)C1=O)=[O:32]>>[NH2:41][CH2:40][C@@H:34]1[C@H:35]([CH3:39])[CH2:36][CH2:37][CH2:38][N:33]1[C:31]([C:30]1[CH:52]=[C:26]([F:25])[CH:27]=[CH:28][C:29]=1[C:53]1[N:54]=[CH:55][CH:56]=[CH:57][N:58]=1)=[O:32]
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-(((2S,3R)-1-(5-fluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione. ESI-MS (m/z): 329 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:26])([F:25])[C:13]([NH:15][C:16]1[CH:21]=[C:20]([NH:22][CH3:23])[CH:19]=[CH:18][C:17]=1[F:24])=[O:14]>CN(C)C=O.C(OCC)(=O)C>[F:26][C:12]([F:11])([F:25])[C:13]([NH:15][C:16]1[CH:21]=[C:20]([N:22]([CH3:23])[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:19]=[CH:18][C:17]=1[F:24])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNc1ccc(F)c(NC(=O)C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A solution of 2-chloro-5-nitropyridine (201 mg, 1.27 mmol) and 2,2,2-trifluoro-N-[2-fluoro-5-(methylamino)phenyl]acetamide (300 mg, 1.27 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 140° C. for 22 hr. The reaction mixture was cooled to room temperature, suspended in ethyl acetate (5 mL), washed with saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 ml), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate/hexane to give the title compound (221 mg, 49%) as yellow crystals.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:26]([NH:28][C@H:29]([C:45]([O:47]CC1C=CC=CC=1)=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34]C(OCC1C=CC=CC=1)=O)=[O:27])[CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)=[O:17])[CH2:7][O:8]CC1C=CC=CC=1)=[O:4].CO.C(O)(=O)C.O>[H][H].[Pd]>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:26]([NH:28][C@H:29]([C:45]([OH:47])=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])=[O:27])[CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)=[O:17])[CH2:7][OH:8])=[O:4]
Reactant: [H][H]
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: NCCCC[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)CN)C(=O)O
Yield: 70.7 %

Procedure:
10.5 g of palladium-on-charcoal was added to 23.2 g of Z-Gly-Ser(Bzl)-His-Lys(Z)-OBzl (Compound 11) suspended in a mixed solvent of 160 ml of methanol, 40 ml of acetic acid and 20 ml of water, and stirring was continued under atmospheric pressure in hydrogen atmosphere for 38 hours. After the catalyst was filtered off, the filtrate was washed with water and concentrated. The crude product was dissolved in water and eluted with 0.5N ammonia water using a strongly acidic ion exchange resin (NH4 +type). The eluate was concentrated and crystallized to obtain 8.0 g of Gly-Ser-His-Lys (Compound 20).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH2:6][CH3:7].[C:16](Cl)(=[O:19])[CH2:17][CH3:18].Cl>C(=S)=S>[C:5]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Nc1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)Nc1ccc(C(=O)CC)cc1
Yield: 51.9 %

Procedure:
Aluminum chloride (600 g, 4.50 mol) is added in portion to a cold (0°-10° C.) stirred solution of propionanilide (230 g, 1.54 mol) and of propionyl chloride (297 g, 3.2 mol) in carbon disulphide (600 ml). The reaction mixture is heated at reflux for 24 h. It is poured into a mixture of hydrochloric acid and crushed ice, and extracted with methylene chloride. The organic phase is washed with a 1% sodium hydrogen carbonate solution, with water, dried (Na2SO4) and filtered. Evaporation of the solvent under reduced pressure gives 1-(4'-propionamidophenyl)-propan-1-one (165 g, 0.8 mol, yield 52%) m.p. 154°-155° C.